Liquid dispensing apparatus and methods

ABSTRACT

The invention provides methods and apparatus for nebulizing liquids. In one exemplary embodiment, an apparatus is provided which comprises a thin shell member having a front surface, a rear surface, and a plurality of apertures extending therebetween. The apertures are tapered to narrow from the rear surface to the front surface. A liquid supplier is further provided which delivers a predetermined unit volume of liquid to the rear surface. A vibrator vibrates the thin shell member to eject liquid droplets from the front surface of the thin shell member.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 08/521,641, filed Aug. 31, 1995, the completedisclosure of which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the field of therapeutic drugdelivery, and in particular to the delivery of therapeutic liquids tothe respiratory system.

A wide variety of procedures have been proposed to deliver a drug to apatient. Of particular interest to the present invention are drugdelivery procedures where the drug is in liquid form and is delivered tothe patient's lungs. Effective intrapulmonary drug delivery depends on avariety of factors, some of which can be controlled by the clinician orscientist and others that are uncontrollable. Uncontrollable factorsinclude, among others, the airway geometry of the patient's respiratorytract and lung and other respiratory diseases. Of the controllablefactors, two are of particular interest. The first is the droplet sizeand droplet size distribution. The second is the breathing pattern.

A major factor governing the effectiveness of drug deposition in thelungs is the size of the inspired particles. Depending on the particlesize, total deposition in various regions of the lung may vary from 11%to 98%. See Heyder et al., Aerosol Sci., 1986, 17, 811-825, thedisclosure of which is herein incorporated by reference. Therefore,proper selection of particle size provides a way to target liquiddroplets to a desired lung region. It is particularly difficult,however, to generate a liquid spray in which all the droplets will havethe same size or the same aerodynamic behavior such that drug depositionin the desirable lung region is predictable.

A parameter that may be used to define droplet size is the respirablefraction (RF). The respirable fraction (RF) is defined as the fractionof the mass of aerosol droplets falling between a particular size range,usually in the range from about 1 μm to 6 μm. See D. C. Cipolla, et al.,Assessment of Aerosol Delivery Systems for Recombinant HumanDeoxyribonuclease, S.T.P. Pharma Sciences 4(1) 50-62, 1994, thedisclosure of which is herein incorporated by reference. As usedhereinafter, the term respirable fraction (RF) will include thepercentage of droplets having sizes falling in the range of from about 1μm to 6 μm. Another parameter that may be used to evaluate nebulizationperformance is the efficiency (E). The efficiency (E) of a nebulizer isthe amount of liquid which is actually aerosolized and leaves thenebulizer in aerosolized form as compared to the amount of liquid thatis initially supplied to the nebulizer. See D. C. Cipolla, et al.,Assessment of Aerosol Delivery Systems for Recombinant HumanDeoxyribonuclease, S.T.P. Pharma Sciences 4(1) 50-62, 1994. Stillanother parameter that may be used to measure the performance ofnebulizers is the delivery percentage (D) which is the respirablefraction (RF) multiplied by the efficiency (E). See D. C. Cipolla, etal., Assessment of Aerosol Delivery Systems for Recombinant HumanDeoxyribonuclease, S.T.P. Pharma Sciences 4(1) 50-62, 1994.

A variety of inhalation devices have been proposed including air jetnebulizers, ultrasonic nebulizers, and metered dose inhalers (MDIs). Airjet nebulizers usually utilize a high pressure air compressor and abaffle system that separates the small particles from the spray.Ultrasonic nebulizers generate ultrasonic waves with an oscillatingpiezoelectric crystal to produce liquid droplets. Another type ofultrasonic nebulizer of interest is described in U.S. Pat. Nos.5,261,601 and 4,533,082. This nebulizer includes a housing that definesa chamber for holding a quantity of liquid to be dispensed. A perforatedmembrane is held over the chamber and defines a front wall of thechamber, with the rear surface of the membrane being in constant contactwith the reservoir of liquid held in the chamber. The apparatus furtherincludes an ultrasonic vibrator connected to the housing to vibrate theperforated membrane. Typical MDIs usually employ a gas propellant, suchas CFC, which carries the therapeutic substance and is sprayed into themouth of the patient.

Most commercially available inhalers produce sprays having a respirablefraction (RF) of 80% or less, with ultrasonic nebulizers usually havinga respirable fraction (RF) of less than about 50%, thereby making dosingcontrol difficult and inaccurate. Presently, most commercially availableinhalers also have a poor efficiency (E), usually less than about 60%.See D. C. Cipolla, et al., Assessment of Aerosol Delivery Systems forRecombinant Human Deoxyribonuclease, S.T.P. Pharma Sciences 4(1) 50-62,1994. Such inefficiency often results from the construction of thenebulizer since a certain amount cannot be nebulized and remains withinthe device. Since most commercially available nebulizers have both apoor respirable fraction (RF) and a poor efficiency (E), the deliverypercentage (D) is also poor. Therefore, such inhalers have generally notbeen used for delivery of drugs that have potent therapeutic agents suchas hormones and peptides or other drugs having a high level of toxicityand which can be expensive.

The second factor influencing droplet deposition is the patient'sbreathing pattern. Inhalation flow rate affects the probability ofparticle impact, while tidal volume and lung volume affect particleresidence time in each lung region. Therefore, effective dropletdeposition should be adaptable to the inhalation flow rate as well asthe patient's tidal volume and lung volume.

Other important factors often considered when designing an effectivetherapeutic drug delivery system include both cost and convenience. Whennebulizing the medicament, the apparatus involved usually comes incontact with the medicament. Hence, the apparatus will need to besterilized before reuse, or discarded. However, sterilization may not beconvenient for a hand held portable device. Disposal can also beexpensive, particularly when the apparatus includes a piezoelectriccrystal for nebulizing the liquid.

It would therefore be desirable to provide improved apparatus andmethods for the delivery of liquids to the respiratory system. Suchapparatus and methods should be capable of producing a spray which maypredictably be deposited in selected regions of the lungs. Further, itwould be desirable if such a spray were produced from a small volume ofliquid. Moreover, it would be desirable if the apparatus and methodsprovided for a controlled drug delivery rate, preferably being based onthe rate of inspiratory air flow generated during inhalation. Finally,it would be desirable if such methods and devices were inexpensive,efficient, and easy to use.

2. Brief Description of the Background Art

U.S. Pat. No. 4,533,082 describes a vibrating orifice apparatus with amultiplicity of apertures for producing liquid droplets.

As previously described, U.S. Pat. No. 5,261,601 describes an atomizerhaving a membrane covering a liquid chamber.

Apparatus for atomizing liquids such as liquid fuel, water, liquid drugsare described in U.S. Pat. Nos. 3,812,854; 4,159,803; 4,300,546;4,334,531; 4,465,234; 4,632,311; 4,338,576; and 4,850,534.

D. C. Cipolla, et al., Assessment of Aerosol Delivery Systems forRecombinant Human Deoxyribonuclease, S.T.P. Pharma Sciences 4(1) 50-62,1994, previously incorporated by reference, describes various inhalationdevices and provides selected data on their efficiency (E) andrespirable fraction (RF) values.

Anthony J. Hickey, Ed., Pharmaceutical Inhalation Aerosol Technology,Drugs and the Pharmaceutical Sciences, Vol. 54, pages 172-173, describesa container and a metering valve for an MDI. The container isspecifically designed to hold a propellant to produce a spray.

SUMMARY OF THE INVENTION

The present invention provides methods and apparatus for the delivery oftherapeutic liquids to the respiratory system of a patient. In oneexemplary embodiment, the apparatus of the present invention ischaracterized in that it is able to produce a spray having a respirablefraction (RF) of greater than about 70%, preferably more than about 80%,and most preferably more than about 90%. Preferably, the apparatus willeject the liquid at a flow rate of at least about 5 μl/sec, andpreferably more than about 10 μl/sec. By producing such a spray, theaerodynamic behavior of all the droplets will be substantially the same,thereby enabling the apparatus to be useful in intrapulmonary drugdelivery.

The apparatus will preferably include a vibratable non-planar surface ornon-planar member with apertures extending therethrough. The non-planarmember will preferably comprise a rigid thin shell member having a frontsurface, a rear surface, and a plurality of apertures extendingtherebetween. The apertures are tapered so that they narrow from therear surface to the front surface. A liquid supplier is provided whichdelivers liquid to the rear surface such that substantially all of thedelivered liquid adheres to the thin shell member, and particularlywithin the large opening of the tapered apertures, by surface tension,i.e. in surface tension contact. A vibrator is further provided whichvibrates the thin shell member to eject liquid droplets from the frontsurface of the thin shell member. Preferably, the apertures will beconfigured to eject liquid droplets having a respirable fraction (RF) ofgreater than about 70%, preferably more than about 80%, and mostpreferably more than about 90%. In another preferable aspect, theapparatus will have an efficiency (E) at or closely approaching 100%,i.e. substantially all liquid supplied to the rear surface will beaerosolized and will be available for inhalation. In this way, thedelivery percentage (D) will usually be about the same as the respirablefraction (RF), i.e. greater than about 70%.

In one exemplary aspect, the size of the apertures at the front surfaceis in the range from about 1 μm to 6 μm, with the apertures have a slopeat the front surface of about 10° or greater relative to a central axisof the apertures, preferably being in the range from about 10° to 20°relative to the central axis of the apertures, and more preferably beingin the range from about 10° to 15° relative to the central axis.Preferably, the thin shell member will have a thickness of about 50 μmto about 100 μm, more preferably from about 75 μm to about 100 μm whichprovides the thin shell member with sufficient rigidity to vibrate inunison and provides sufficient aperture volume. In the presentinvention, ejection of droplets is developed due to the solid/fluidinteraction inside the aperture, i.e. the interaction of the liquidagainst the tapered wall of the aperture. The cross sectional geometryof the aperture is therefore important. For example, if the aperture hasa straight cylindrical wall with a slope of 0° relative to the centralaxis (or a 90° slope relative to the front surface of the thin shellmember), ejection will not occur. Instead, the vibratory motion willcause the liquid to break loose from the vibratory surface so that itwill not eject through the aperture.

For apertures smaller than 6 μm, the slope near the exit opening of theaperture is particularly important because the discharge coefficient ofsuch an aperture is substantially smaller than for larger apertures. Forapertures smaller than 6 μm, a slight variation in the slope near thesmall opening of the aperture will make significant influence onejection of droplets because the tapered shape near the openingincreases the surface area that is subjected to solid/fluid interactionnear the exit opening. For example, vibration of the thin shell memberwhen the apertures have a slope of 20° (relative to the central axis ofthe apertures) near the small opening produces 10 times more dropletsthan when the apertures are at right angles to the front surface. Inthis manner, a high flow rate can be achieved using a small thin shellmember. A small thin shell member is desirable in that it has higherstructural rigidity which assists in producing a fine spray as describedhereinafter.

In another exemplary aspect, the thin shell member is hemispherical,parabolic, arc shaped, or curved in geometry, with the large opening ofeach aperture being located at the concave side, and the small openingof each aperture being located at the convex side. The thin shell memberis preferably formed to have a low mass and a very high stiffens whichcauses the thin shell member to oscillate as a rigid body, i.e.homogeneously. In this way, all the apertures in the thin shell memberare subject to the same amplitude so that droplets may be produced witha uniform size and with a desired respiratory fraction.

In one particular embodiment, the invention provides an apparatus fornebulizing a liquid having a housing with a proximal end and a distalend. A non-planar member, and preferably a thin shell member, is mountedwithin the housing, with thin shell member having a plurality ofapertures for nebulizing the liquid upon vibration of the thin shellmember. A vibrator is provided and is removably attached about thehousing which vibrates the thin shell member. Preferably, the thin shellmember is mounted within a dynamically isolated portion of the housing.In this manner, the vibration is not transmitted to the housing allowingthe vibrator to be dismantled and reinstalled over the housing asdesired.

Advantageously, the elements that come in contact with the mouth of thepatient or with of the therapeutic liquid are held within the housing.Prior to use, the housing is connected to the vibrator which transmitsvibratory motion to the thin shell member inside the housing to produceejection of droplets which are then entrained in the inspiratory airflow. In this manner, the vibrator will not come into contact with theliquid, thereby allowing the vibrator to be reused with a new anduncontaminated housing. Such a configuration provides an economicalnebulizing apparatus since the relatively expensive vibrator may bereused.

In a further exemplary embodiment of the present invention, an apparatusis provided which ejects a liquid spray at a rate synchronized with theinspiratory flow created during inhalation so the that ejection rate isproportional to the inspiratory flow rate. The apparatus includes ahousing having a distal end and a mouthpiece at a proximal end. Anon-planar member, and preferably a thin shell member, is mounted withinthe housing, with the thin shell member having a plurality of apertures.A vibrator is provided to vibrate the thin shell member and to ejectliquid from the apertures. An acoustic chamber is provided within thehousing which produces an audible signal during inhalation from themouthpiece. Further provided is a controller for controlling the rate ofthin shell member vibration upon detection of the audible signal.Preferably, the controller includes a microphone which detects theaudible signal so that an electrical signal may be sent to the vibrator.

In this manner, the patient may simply breath through the mouthpiece (ora nasal adapter) to control the rate of droplet production. Therespiratory flow passes through the acoustic chamber which produces theacoustic tone which is proportional to the inspiratory flow rate. Thus,the frequency of the acoustic tone indicates the inspiratory flow rateat any instant of the breathing cycle. Integration of the flow rate withtime produces the tidal volume. Both the flow rate and the tidal volumecan then be used to determine when the ejector should eject droplets andat what mass flow rate such that maximum deposition of droplets isobtained. Further, the acoustic tone may be recorded to produce a recordof the breathing pattern of the patient which may be stored in amicroprocessor. This information can be later used to synchronize theejection of droplets for the same patient. Such information may also belater employed for other diagnostic purposes.

The invention further provides a method for nebulizing a liquid.According to the method, a non-planar member, preferably a thin shellmember, having a plurality of tapered apertures extending therethroughis vibrated. The apertures in the thin shell member are configured toproduce liquid droplets having a respirable fraction (RF) of greaterthan about 70%, preferably more than about 80%, and most preferably morethan about 90%. In a preferable aspect, liquid is supplied to the thinshell member such that substantially all of the delivered liquid adheresto the thin shell member by surface tension. In this manner, the needfor a container or a chamber to hold the liquid against the thin shellmember is eliminated. Instead, the liquid is open to the atmosphere andis not subjected to pressurization or reflecting acoustic waves that maybe produced within an adjacent chamber. Preferably, liquid will besupplied to the thin shell member by squeezing a liquid reservoir whichdispenses a discrete volume of liquid onto the thin shell member.Usually, substantially all liquid delivered to the thin shell memberwill be transformed into liquid droplets that are available forinhalation, i.e. the efficiency (E) will be at or near 100%. In thisway, the delivery percentage (D) will be substantially the same as therespirable fraction (RF).

In another aspect, the method provides for producing the liquid dropletsat a rate greater than about 5 μliters per second. In another aspect,the vibrating step further comprises vibrating substantially all of theapertures in the thin shell member in unison. Preferably, the thin shellmember will be vibrated at a frequency in the range from about 45 kHz to200 kHz. In yet another aspect, the thin shell member is held within ahousing having a mouthpiece, and the thin shell member is vibrated at arate corresponding to an inspiratory flow rate through the mouthpiece.In one preferable aspect, the thin shell member is vibrated only duringinhalation from the mouthpiece. Control of shell member vibration inthis manner may be accomplished by producing an audible signal duringinhalation and detecting the produced signal.

In one particular aspect, the vibrating step comprises removablyattaching a vibrating source about a housing enclosing the thin shellmember and actuating the vibrating source. Optionally, the vibratingsource may be removed from the housing and the housing discarded afteruse.

The invention provides a further exemplary method for delivering aliquid to the lungs of a patient. According to the method, a housing isprovided having a proximal end and a distal end. Liquid is supplied toan thin shell member disposed within the housing, with the thin shellmember having a plurality of tapered apertures extending therethrough.The patient then inhales from the proximal end of the housing at aselected inspiratory flow rate, and the thin shell member is vibrated toeject the liquid at a rate corresponding to the inspiratory flow rate.

In one aspect of the method, the inspiratory flow rate is variable. Inanother aspect, the vibrating step further comprises ejecting the liquidonly during inhalation. In still a further aspect, an audible signal isproduced during inhalation and the produced signal is detected tocontrol the rate of vibration of the thin shell member.

The thin shell member will preferably be vibrated to produce liquiddroplets having a respirable fraction (RF) of greater than about 70%,preferably more than about 80%, and most preferably more than about 90%.In another preferable aspect, liquid will be supplied to the thin shellmember such that substantially all of the delivered liquid adheres tothe thin shell member by surface tension. Preferably, substantially allof the apertures in the thin shell member will be vibrated in unison.

The invention further provides an exemplary apparatus for nebulizing aliquid. The apparatus is particularly useful in accurately dispensingdiscrete quantities of a liquid, such as a single unit dosage of aliquid medicament. The apparatus comprises a thin shell membercomprising a front surface, a rear surface, and a plurality of aperturesextending therebetween. The apertures are tapered to narrow from therear surface to the front surface. A liquid supplier is provided todeliver a predetermined unit volume of liquid to the rear surface. Avibrator vibrates the thin shell member to eject liquid droplets fromthe front surface of the thin shell member. Hence, by delivering only aunit volume of liquid to the rear surface and ejecting the entire unitvolume, an apparatus for precisely nebulizing a known unit volume ofliquid is provided.

In one exemplary aspect, the liquid supplier comprises a canister whichholds the liquid under pressure. Usually, the canister will comprise astorage reservoir and a valve which allows the predetermined unit volumeof liquid to be delivered from the canister when the valve is in an openposition. In a preferable aspect, the valve comprises a chamber having apiston therein and a stem having a proximal end and a distal end. Thestem includes an elongate groove at the distal end which places thestorage reservoir and the chamber in fluid communication when the valveis in a closed position so that the chamber may be filled with liquidfrom the storage reservoir. The stem further includes a lumen at theproximal end which is placed in fluid communication with the chamberwhen the valve is in the open position such that a unit volume of theliquid within the chamber is forced out of the lumen and onto the rearsurface of the thin shell member upon translation of the piston.

In another particular aspect, a spring is included adjacent the pistonso that the piston may be automatically translated to force the unitvolume of liquid from the chamber when the valve is in the openposition. The pressure within the storage reservoir then compresses thespring to allow the chamber to be refilled with liquid from the storagereservoir when the valve is in the closed position.

In still another aspect, an acoustical sensor is provided which detectswhen the unit volume of liquid has been ejected from the thin shellmember. Preferably, the acoustical sensor comprises a piezoelectricelement. In this manner, a user may be informed as to whether all of theliquid supplied to the thin shell member has been nebulized. In yetanother aspect, the apparatus includes a mouthpiece and a means foractuating the vibrator when a patient begins to inhale from themouthpiece.

The invention also provides an exemplary method for nebulizing a singleunit volume of liquid, such as a unit dosage of a liquid medicament.According to the method, a thin shell member is provided which comprisesa front surface, a rear surface, and a plurality of apertures extendingtherebetween. The apertures are tapered to narrow from the rear surfaceto the front surface. A valve is then opened to deliver a unit volume ofthe liquid from a container and to the rear surface of the thin shellmember. The thin shell member is vibrated until substantially all of theunit volume of the liquid on the rear surface is ejected from the frontsurface.

In one particular aspect, a piston is translated within the containersufficient to expel the unit volume of the liquid from the container andonto the rear surface when the valve is opened. Preferably, the valve isspring biased so that the piston will automatically translate uponopening of the valve. In another aspect, the container holds the liquidunder pressure so that the piston will be translated in an oppositedirection by force of the liquid to compress the spring when the valveis closed. In this way, the container will be refilled when the valve isclosed.

In one exemplary embodiment, the container comprises a canister whichholds the liquid in a pressurized storage reservoir. The valve comprisesa chamber having a spring loaded piston therein and a stem having aproximal end and a distal end and an elongate groove at the distal endwhich places the storage reservoir and the chamber in fluidcommunication when the valve is in a closed position. In this manner,opening of the valve is accomplished by depressing the valve stem toplace a lumen at the proximal end of the stem in fluid communicationwith the chamber so that a unit volume of the liquid within the chamberwill be forced out the lumen upon translation of the piston.

In another particular aspect, a step is provided for sensing when theunit volume of liquid has been ejected from the thin shell member.Preferably, such sensing is accomplished by detecting a change of anacoustical signal generated by the vibrating thin shell member toindicate when the unit volume has been ejected. Preferably, theacoustical signal is sensed with a piezoelectric element.

In yet another aspect, a mouthpiece is provided which is spaced-apartfrom the thin shell member. With such a configuration, a step isprovided for sensing when a patient inhales from the mouthpiece andvibrating the thin shell member only during inhalation. In still anotheraspect, the unit volume of liquid that is nebulized is in the range fromabout 20 μl to about 100 μl.

The invention still further provides another exemplary apparatus fornebulizing a liquid. The apparatus comprises a thin shell membercomprising a front surface, a rear surface, and a plurality of aperturesextending therebetween, with apertures being tapered to narrow from therear surface to the front surface. A liquid reservoir is provided, and acapillary system is in fluid communication with the liquid reservoir.The capillary system is disposed to draw liquid from the reservoir bycapillary action for delivery to the rear surface of the thin shellmember. A vibrator is also provided and vibrates the thin shell memberto eject liquid droplets from the front surface of the thin shellmember.

In one preferable aspect, the capillary system comprises a wickingmember having a bottom end within the liquid reservoir and a deliveryend near the rear surface of the thin shell member. An outer member isspaced-apart from the wicking member by a capillary gap so that liquidfrom the reservoir may be drawn through the capillary gap and toward thedelivery end by capillary action. Preferably, the wicking member furtherincludes at least one capillary channel at the delivery end so thatliquid delivered from the capillary gap may continue its travel to therear surface of the thin shell member through the capillary channel. Inanother preferable aspect, a bottom portion of the wicking member iscylindrical in geometry, and the outer member includes an annular bodywhich surrounds the wicking member.

In one exemplary aspect, the apparatus further includes a housing havinga chamber and a mouthpiece, with the outer member being attached to thehousing. The wicking member is attached to the liquid reservoir which inturn is detachably secured to the housing so that the liquid reservoirmay be separated from the housing. In another aspect, the wicking memberincludes a flexible portion so that it may axially flex upon contactwith the vibrating member. In this way, contact of the wicking memberwill not interfere with the performance of the vibratable member.

In still yet another aspect, the liquid reservoir has a concave shapeand includes capillary channels which move the liquid toward thecapillary gap between the outer member and the wicking member. A powersupply is further provided which supplies power to the vibrator. Thepower supply may comprise a battery, a rechargeable battery, an AC or aDC power source, or the like.

The invention still further provides an exemplary method for nebulizinga liquid by providing a thin shell member comprising a front surface, arear surface, and a plurality of apertures extending therebetween. Theapertures are tapered to narrow from the rear surface to the frontsurface. Liquid is drawn from a liquid reservoir by capillary action toplace the liquid in contact with the rear surface of the thin shellmember. The thin shell member is vibrated to eject the liquid on therear surface from the front surface, with liquid being continuouslysupplied from the liquid reservoir to the rear surface as the thin shellmember is vibrated. In this manner, substantially all of the liquidwithin the reservoir may be nebulized.

In one exemplary aspect, the capillary action is provided by a capillarygap between a wicking member and an outer member, with the wickingmember having a bottom end within the liquid reservoir and a deliveryend near the rear surface of the thin shell member. The capillary actionmay optionally be augmented by providing at least one capillary channelat the delivery end of the wicking member so that liquid from thecapillary gap may continue its travel to the thin shell member.

In another aspect of the method, a housing is provided having a chamber,a mouthpiece, the outer member, and the vibratable member. In thismanner, the reservoir may be attached to the housing prior to vibratingthe vibratable member. After nebulizing the liquid, the housing may bedetached from the reservoir so that the housing and reservoir may bewashed. In another exemplary aspect, the housing may be titled whilenebulizing the liquid, thereby allowing a patient to inhale from themouthpiece while lying down. In still another aspect, at least some ofthe liquid is transferred from the liquid reservoir and to the capillarygap by capillary action.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top view of a disposable mouthpiece assembly of a nebulizingapparatus according to the present invention.

FIG. 2 is a cross-sectional view of the mouthpiece assembly of FIG. 1.

FIG. 3 is a side view of an exemplary nebulizing apparatus having anoscillator assembly attached about the mouthpiece assembly of FIG. 1according to the present invention.

FIG. 4 is a bottom view of a vibratory cantilever beam of the oscillatorassembly of FIG. 3.

FIG. 5 illustrates a side view of the cantilever beam of FIG. 4, withthe mode of vibration being shown in phantom line.

FIG. 6 is a cross-sectional side view of an exemplary aperture in a thinshell member according to the present invention.

FIG. 7 is a cross-sectional side view of an alternative aperture in athin shell member according to the present invention.

FIG. 8 is a graph illustrating the relationship between the acousticfrequency produced by an acoustic chamber within the mouthpiece assemblyof FIG. 1 and the inspiratory flow rate through the mouthpiece assemblyaccording to the present invention.

FIG. 9 is a schematic view of a system for supplying a predeterminedunit volume of liquid to a rear surface of a vibratable member accordingto the present invention.

FIG. 10 illustrates the system of FIG. 9 shown with a piston beingtranslated to deliver the predetermined unit volume of liquid to therear surface according to the present invention.

FIG. 11 is a perspective view of an exemplary apparatus for nebulizing apredetermined unit volume of liquid according to the present invention.

FIG. 12 is a perspective view of the apparatus of FIG. 11 illustratingan AC flip blade which may be inserted into an AC outlet according tothe present invention.

FIG. 13 is a cross-sectional side view of the apparatus of the FIG. 11.

FIG. 13A is a side view of a thin shell member of the apparatus of FIG.13.

FIG. 14 is an exploded view of a canister and a valve of the apparatusof FIG. 13.

FIG. 15 is a cross-sectional side view of the canister and valve of FIG.14 with the valve shown in a closed position.

FIG. 16 illustrates the canister and valve of FIG. 15 in an openposition.

FIG. 17 is an exploded perspective view of an alternative apparatus fornebulizing a liquid according to the present invention.

FIG. 18 is a perspective view of a wicking member of the apparatus ofFIG. 17.

FIG. 19 is a cross-sectional side view of the apparatus of FIG. 17.

FIG. 20 is a more detailed view of a capillary system of the apparatusof FIG. 19.

FIG. 21 illustrates the apparatus of FIG. 19 with the wicking systembeing detached from the apparatus housing.

FIG. 22 illustrates the apparatus of FIG. 19 with a DC car adapter.

FIG. 23 is a side view of an AC plug that may be used with the apparatusof FIG. 19.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The invention provides methods and apparatus for producing a very finespray useful in pulmonary drug delivery procedures. The inventionprovides for producing a spray having a respirable fraction (RF) ofgreater than about 70%, preferably more than about 80%, and mostpreferably more than about 90%. The efficiency (E) of the nebulizationapparatus will usually be at or near 100%, leading to a deliverypercentage (D) which is substantially the same as the respirablefraction (RF). Such a spray will preferably be produced at a flow rateof at least about 5 μl per second, and more preferably at least about 10μl per second. In this manner, a spray of a selected size is producedwhere the aerodynamic behavior of all the droplets is substantially thesame, thereby enabling the spray to be predictably deposited in selectedregions of the lungs during intrapulmonary drug delivery procedures.

The invention may be employed to deliver a wide variety of drugs to therespiratory system, and will preferably be used to deliver drugs havingpotent therapeutic agents, such as hormones, peptides, and other drugsrequiring precise dosing. Liquid drugs which may be nebulized using thepresent invention include drugs in solution form (e.g., in aqueoussolution, ethanol solution, aqueous/ethanol mixture solution, and thelike), in colloidal suspension form, and the like.

The invention will preferably be configured to supply the spray upondemand, i.e., the spray will be produced and delivered only uponinhalation by the patient. Further, such a spray will preferably beproduced and delivered at a rate corresponding to the inhalation orinspiratory flow rate produced by the patient when inhaling the spray.In this manner, the spray will be produced only when the patient isinhaling, and will preferably be produced at a rate corresponding to theinhalation rate.

The invention will provide such a spray by providing the liquid to avibratable non-planar member, which is preferably a thin shell memberhaving a plurality of apertures. Liquid is preferably supplied to thethin shell member such that substantially all of the delivered liquidwill adhere to the thin shell member by surface tension. Upon vibrationof the thin shell member, the adhering liquid will be ejected throughthe apertures to form the fine spray. In this manner, a precise andcontrolled amount of liquid drug can be supplied to the thin shellmember for nebulization, thereby eliminating the need for a fluidreservoir to be placed against the thin shell member.

Apertures in the thin shell member of the invention will preferably betapered in geometry, with the smaller end of the aperture being locatedat a front surface of the thin shell member and the larger opening ofthe aperture being at the rear surface of the thin shell member. Thesize of the apertures at the front surface will preferably be in therange from about 1 μm to 6 μm, with the slope of the apertures at thefront surface being in the range from about 10° or greater relative to acentral axis extending through the apertures, preferably from about 10°to 20° relative to the central axis extending through the apertures, andmore preferably being in the range from about 10° to 15° relative to thecentral axis.

Referring now to the figures, an exemplary embodiment of a nebulizingapparatus 10 will be described. As best illustrated in FIG. 3, thenebulizing apparatus 10 includes a disposable mouthpiece assembly 12 anda removable oscillating assembly 14. Referring to FIG. 1, constructionof the mouthpiece assembly 12 will be described. The mouthpiece assembly12 includes an elongate tubular housing 16 having a proximal end 18 anda distal end 20. At the distal end 20 is a mouthpiece 22, while a liquidsupply cartridge 24 is at the proximal end 18. As will be described ingreater detail hereinafter, a carrier plate 26 extends from the housing16 and is provided to hold a thin shell member within the housing 16. Anelastomeric O-ring 28 is placed adjacent the carrier plate 26 and ispositioned against a vibrating beam as described in greater detailhereinafter. To dynamically isolate the carrier plate 26, the housing 12is preferably constructed of an elastomeric material, preferably havinga modulus of elasticity of about 100 psi to 150 psi.

Referring to FIG. 2, the interior of the mouthpiece assembly 12 will bedescribed. The tubular housing 16 forms a central chamber 32 having anopening 34 at the mouthpiece 22. Annularly extending into the centralchamber 32 is the carrier plate 26. In turn, the carrier plate 26 isattached about a thin shell member 36 having a front surface 38 and arear surface 40. Extending between the front surface 38 and rear surface40 are a plurality of tapered apertures (not shown) having the smalleropening at the front surface 38 and the larger opening at the rearsurface 40. Upon vibration of the carrier plate 26, the thin shellmember 36, is vibrated so that liquid may be ejected through theapertures and from the front surface 38 as described hereinafter.

An amount of liquid 42 is supplied to the rear surface 40 from theliquid supply cartridge 24. The liquid cartridge 24 includes a divider44 that separates the liquid supply cartridge 24 into an air volume 46and a liquid volume 48. To dispense liquid from the liquid volume 48,the liquid supply cartridge 24 is squeezed to force liquid in the liquidvolume 48 through a nozzle 50 where it comes into contact with the rearsurface 40 of the thin shell member 36. The cartridge 24 becomespermanently deformed when squeezed so that the liquid 42 delivered tothe rear surface 40 will not be withdrawn back into the liquid volume48. The size of the air volume 46 will be configured such that all ofthe liquid within the liquid volume 48 will be transferred from theliquid volume 48 when the cartridge 24 is squeezed.

The liquid 42 delivered from the supply cartridge 24 will usually beheld to the rear surface 40 solely by surface tension forces. In thisway, the liquid 42 may remain in contact with the rear surface 40 untilejected and without the need for a separate chamber to hold the liquid42 against the rear surface 40. To eject the liquid 42 from the frontsurface 38, the carrier plate 26 is vibrated to in turn vibrate the thinshell member 36. The liquid 42 adhering to the rear surface then passesthrough the apertures and from the front surface 38 as described in U.S.Pat. No. 5,164,740 and copending application Ser. No. 08/163,850 filedDec. 7, 1993 and 08/417,311, filed Apr. 5, 1995, the entire disclosuresof which are herein incorporated by reference.

The thin shell member 36 is preferably formed of a thin, rigid materialhaving a hemispherical geometry. Alternatively, the thin shell member 36may be parabolic, arc shaped, or curved in geometry. The thin shellmember 36 will have a very high bending stiffness which will allow it tofollow the vibratory motion of the carrier plate 26 as a rigid body. Inthis way, the entire thin shell member 36 will vibrate in unison so thatall apertures are subject to the same amplitude of vibration. Suchvibration will assist in ejecting uniformly sized droplets (i.e. havinga respirable fraction (RF) of greater than about 70%, preferably morethan about 80%, and most preferably more than about 90%) simultaneouslyfrom most or all of the apertures. The spray produced by the thin shellmember 36 is dispensed into the central chamber 32 in the direction ofthe opening 34. In this manner, as the patient inhales from themouthpiece 22, the spray within the central chamber 32 will be drawninto the patient's lungs.

To control the time and/or rate at which the spray is produced, themouthpiece assembly 12 further includes an acoustic chamber 52 havingholes 54 and 56. Upon inhalation, air within the central chamber 32passes through the holes 54 and 56 to produce an acoustic tone. Thistone may be detected as described in greater detail hereinafter and usedto determine both when the patient is inhaling and the patient'sinspiratory flow rate. Such a signal may then be used to actuate theoscillating assembly which vibrates the thin shell member 36. Such asignal may be employed to control the time at which the shell member 36is vibrated, e.g., such as only during inhalation. Alternatively, such asignal may also be employed to vibrate the thin shell member 36 at afrequency corresponding to the inspiratory flow rate. FIG. 8 illustratesone example of acoustical frequencies that may be produced for variousinspiratory flow rates. For instance, an inspiratory flow rate of about20 liters per second will generate an acoustical frequency of about 15kHz. In turn, the detected frequency may be employed to drive the thinshell member 36.

Referring now to FIG. 3, operation of the combined mouthpiece assembly12 and the oscillating assembly 14 will be described. The mouthpieceassembly 12 will preferably be constructed so that it may be removablyattached to the oscillating assembly 14. In this manner, the mouthpieceassembly 12 may be discarded after use, while the oscillating assembly14 which will not come into contact with the liquid may be reused. Oneparticular advantage of such a configuration is that the mouthpieceassembly 12 may be constructed relatively inexpensively by not includingan internal oscillator. Since the oscillating assembly 14 may be reused,costs to the patient are reduced.

The mouthpiece assembly 12 is connected to the oscillating assembly 14by sliding the proximal end 18 of the mouthpiece assembly 12 through anopening 58 (see FIG. 5) in a cantilever beam 60 of the oscillatingassembly 14 until the o-ring 28 engages and is secured against thecantilever beam 60 as indicated by the arrows. A latching mechanism (notshown) may optionally be provided to removably latch the mouthpieceassembly 12 to the cantilever beam 60.

The cantilever beam 60 is provided with a free end 62 and a fixed end64. The fixed end 64 is attached to an electronic circuit board 66 by apair of screws 65, thus limiting the ability of the fixed end 64 tovibrate. On the other hand, the free end 62 which is attached to themouthpiece assembly 12 is free to vibrate. A piezoelectric element 68 isbonded to the beam 60 and transmits vibratory motion to the beam 60. Thedimensions of the beam 60 may be varied depending on the frequency ofvibration. In one particular embodiment which is usually vibrated at 45kHz to 200 kHz, the beam 60 will preferably have a length of about 30 mmto 80 mm, preferably at about 40 mm, a width of about 8 mm to 15 mm,preferably at about 12 mm, and a thickness of about 0.5 mm to 1 mm,preferably at about 0.7 mm. Such a beam will preferably be oscillated ata frequency of about 45 kHz which corresponds to the natural frequencyof the beam. When vibrated, the beam 60 will have an oscillation modeshape 70 as illustrated in phantom line in FIG. 5.

Upon vibration of the cantilever beam 60, the elastomeric material ofthe housing 16 prevents transfer of vibratory energy through the tubularhousing 16. In this manner, only the carrier plate 26 and the adjacentportion of the housing 16 are vibrated so that only minimal energy isneeded to sufficiently vibrate the thin shell member 36. The cantileverbeam 60 will preferably be vibrated to produce an oscillation amplitudeof about 0.001 mm at the free end 62. Such vibration is transferred tothe thin shell member 36 via the carrier plate 26 to produce a finespray particles having a desired respirable fraction (RF).

In one experiment, the apparatus 10 of FIG. 3 was vibrated at afrequency of 45 kHz, and the particle size and distribution was measuredby a particle sizer commercially available from Malvern Instruments Inc.(Southburrow, Mass.). The results indicated that about 94.99% of theparticles were in the range from 1 to 6 micron with a flow rate of about10 cubic μl per second.

To operate the nebulizing apparatus 10, the patient first attaches themouthpiece assembly 12 to the oscillating assembly 14 as previouslydescribed. The liquid supply cartridge 24 is then squeezed to transferthe liquid to the rear surface 38 of the thin shell member 36. Thepatient then places his mouth over the mouthpiece 22 and begins toinhale. As air is drawn through the central chamber 32, an acoustic toneis produced by the acoustic chamber 52. As illustrated in FIG. 3, theacoustic tone may be detected by a microphone 72 on the circuit board66. The detected acoustic signal is then processed by the circuit board66 and is used to drive the piezoelectric element 68 at a frequencyproportional to the acoustical frequency. In this manner, spray beginsto rate that is proportional to the inspiratory flow rate. After thepatient has fully inhaled, the acoustic signal ceases, thereby ceasingvibration of the piezoelectric element 68. If all of the liquid has notbeen dispensed, the patient may again inhale as previously describeduntil all of the liquid has been delivered to the patient's lungs.

Referring to FIG. 6, an exemplary embodiment of an aperture 74 that maybe included in the thin shell member 36 will be described. The aperture74 has a conical shape, with a large opening 76 being at the rearsurface 40 and a small opening 78 being at the front surface 38. At thesmall opening 78, the aperture 74 will have a slope, θ, measuredrelative to a central axis extending through the aperture 74. The slopeθ at the small opening 78 will preferably be in the range from about 10°to 20°, more preferably in the range from about 10° to 15° and mostpreferably at about 15°. As the aperture 74 approaches the large opening76, the slope may increase as illustrated. Preferably, the slope of theaperture 74 at the large opening 76 will be about 45° relative to thecentral axis, although the angle is not as critical as near the smallopening. The slope of the aperture 74 near the small opening 78 isparticularly important since ejection from the thin shell member 36 willoccur at the front surface 36 where the small opening 78 is located. Theslope, θ, should usually be at least about 10° with respect to the axisof the aperture to insure optimal ejection.

Referring to FIG. 7, an alternative aperture 80 for the thin shellmember 36 will be described. The aperture 80 is conical and has a largeopening 82 at the rear surface 40 and a small opening 84 at the frontsurface 38. When viewed in cross-section, the aperture 80 is formed ofportions of two circles, with each circle having the same radius. Thecircles are positioned so that the slope θ at the small opening 84 willbe in the range from about 10° to 20° relative to the central axis, morepreferably from about 10° to 15°, and most preferably at about 12°. Whenthe small opening 84 is sized at about 3 microns and has a taper ofabout 12°, the ejection rate from the small opening 84 is approximately100 times greater than a quadrant-edge aperture having a 0° slope at thesmall opening as described in Jorissen, A. L., Discharged Measurement atLow Reynolds Number, ASME, February 1956, pp. 365-368, the disclosure ofwhich is herein incorporated by reference.

Referring to FIGS. 9 and 10, an exemplary system 100 for delivering apredetermined unit volume of liquid to a vibratable member 102 will bedescribed. Vibratable member 102 vibrates a thin shell member 104similar to the other thin shell members described herein so that liquidplaced in surface tension with the rear side of the thin shell member104 will be ejected from a front side. System 100 is provided so thatonly a predetermined unit volume of liquid will be supplied to the thinshell member 104. In this way, when vibratable member 102 is vibrated,the unit volume of liquid will be nebulized. Such a system is thereforeadvantageous in applications where a known volume of liquid is to benebulized, such as when producing an aerosolized dosage of a medicament.

System 100 is provided with a source of liquid 106 which is preferablyheld under pressure. Liquid from source 106 passes through a line 108,through a valve 110 (shown in an open configuration), through a line112, and into a metering chamber 114. Metering chamber 14 includes aspring biased piston 116 which is moved against a stop 118 when chamber14 is filled with the liquid. When piston 116 is against stop 118,metering chamber 114 contains a unit volume so that when piston 116 isfully translated as shown in FIG. 10, a unit volume of liquid will beexpelled into a line 120. Connected to line 120 is a valve 122 which isin a closed configuration in FIG. 9. In this way, the liquid withinmetering chamber 114 will be prevented from leaving until valve 122 isopened.

When metering chamber 114 is full, valve 110 is closed as shown in FIG.10. Then, when a unit volume of liquid is ready to be supplied to thinshell member 104, valve 122 is opened. When valve 122 is opened, piston116 translates by force of a spring 124 to force a unit volume of liquidout of metering chamber 114. In turn, a unit volume of liquid isdelivered to thin shell member 104 through a line 126. The system lineswill preferably be small enough so that minimal liquid will remain inthe lines after being expelled from chamber 114, thereby allowingsubstantially all of the unit volume to de delivered to thin shellmember 104. This unit volume is in the range from about 30 μl to about70 μl, and more usually about 50 μl in volume and adheres to thin shellmember 104 by surface tension. As vibratable member 102 is vibrated, theunit volume of liquid delivered to thin shell member 114 will benebulized.

Referring now to FIG. 11, an exemplary embodiment of an apparatus 128for nebulizing a unit volume of liquid will be described. Apparatus 128includes a housing 130, a removable top end 132, and a mouthpiece 134.When top end 132 is depressed, a unit volume of a liquid is madeavailable for nebulization as described in greater detail hereinafter.

As best shown in FIG. 12 (which is a rear view of FIG. 11), apparatus128 may optionally include a pair of flip blades 138 which may beinserted into an AC adapter or outlet to recharge batteries 140 (seeFIG. 13) which supply power to apparatus 128. After recharging, flipblades 138 may be rotated and placed within slots 142 for convenientstorage. Although shown with rechargeable batteries, apparatus 128 mayhave power supplied by any of a variety of power sources including DCpower supplies, AC power supplies, batteries, including rechargeablebatteries, and the like.

Referring to FIG. 13, construction of apparatus 128 will be described ingreater detail. Apparatus 128 includes a container 144 having a top end146 and bottom end 148. When within housing 130, top end 146 ispositioned against batteries 140 so that a gap 131 is provided betweentop end 132 and housing 130 as shown. Bottom end 148 includes a valve150 having a stem 152 with a proximal end 154 and a distal end 156.Distal end 156 rests on a shelf 158 so that when top end 132 isdepressed, the gap 131 between top end 132 and housing 130 is closed. Inturn, stem 152 is translated further into container 144 to deliver aunit volume of liquid into a passage 160 where it will be delivered to arear surface of a thin shell member 162 of a vibratable member 164. Thinshell member 162 may be constructed similar to other embodimentsdescribed herein so that when vibratable member 164 is vibrated, liquidon the rear surface of thin shell member 162 will be dispensed from thefront surface. Thin shell member 162 is shown in greater detail in FIG.13A. In FIG. 13A, a side view of thin shell member 162 is shown with aplurality of tapered apertures 163 from which the liquid is ejected aspreviously described with other embodiments.

Vibratable member 164 is caused to vibrate by a piezoelectric element166. Piezoelectric element 166 in turn is electrically connected to aprinted circuit board 168 by wires (not shown), with the circuit board168 having the electronics necessary to vibrate piezoelectric element166. Vibratable member 164 may be constructed similar to and vibrated atfrequencies similar to those previously described herein and in U.S.Pat. No. 5,164,740 and U.S. patent application Ser. No. 08/163,850,filed Dec. 7, 1993 and Ser. No. 08/417,311, filed Apr. 5, 1995,previously incorporated by reference. Power is supplied to circuit board168 from batteries 140, which may optionally be rechargeable aspreviously described.

Vibratable member 164 is fixedly attached housing 130 by a pair ofmounting screws 170 and 172. Vibratable member 164 is bent so that thinshell member 162 will be positioned to eject liquid into mouthpiece 134.

As a patient draws upon mouthpiece 134, air is drawn into housing 130through a plurality of air inlets 174. In this manner, outside airsweeps through an acoustic chamber 176 so that the patient may inhalenebulized liquid produced from the thin shell member 162. Acousticchamber 176 is used in combination with a microphone 178 on circuitboard 168 to control actuation of piezoelectric element 166. Such anoperation is similar to the embodiment of FIGS. 1 and 2 as previouslydescribed. Hence, when a patient inhales from mouthpiece 134, air drawnthrough acoustic chamber 176 will produce an acoustic sound, preferablyoutside the audible range, which is detected by microphone 178. In turn,circuit board 168 sends a signal to actuate piezoelectric element 166 tovibrate vibratable member 164. In this way, liquid is nebulized when thepatient begins to inhale. When inhalation is stopped, microphone 178will detect a stoppage of the acoustical signal so that vibration ofvibratable member 164 will be stopped. The patient may continue toinhale from mouthpiece 134 until the entire unit volume of liquid at therear surface of thin shell member 162 is dispensed. In this way, it maybe assured that only a unit volume of liquid will be delivered to thepatient (and on demand) since only a unit volume of liquid will bedelivered to thin shell member 162. Further, little or no liquid will bewasted since the volume of liquid at the rear surface of thin shellmember 162 will be nebulized only during inhalation from mouthpiece 134.

Apparatus 128 further includes an acoustical sensor 161 to detect whenthe unit volume of liquid has been ejected from thin shell member 162.Sensor 161 preferably comprises a piezoelectric element which vibratesfrom an acoustical signal generated when liquid adheres to the rearsurface of thin shell member 162. When all of the liquid is ejected,sensor 161 will cease to vibrate indicating that all of the liquid hasbeen nebulized.

Referring now to FIGS. 14-16, construction of container 144 and valve150 will be described. Container 144 is constructed of a rigid material,such as aluminum, so that container 144 may hold a volume of liquidunder pressure. Exemplary gases for holding liquid within container 144under pressure include Nitrogen, air, or any inert gases, and the like.It will be understood that while the liquid within container 144 is heldunder pressure, container 144 will not include a propellant solution oran aerosol generating chemical as is typically used with conventionalaerosol devices, such as MDI's. As such, container 144 will bepositioned such that top end 146 is positioned vertically above bottomend 148 (see FIG. 15) so that the liquid will be in contact with valve150.

As previously described, valve 150 includes stem 152 which is secured tocontainer 144 by an insert 180 and a cap 182. 182. Positioned over stem152 is a cylindrical seal 184, an O-ring seal 186, a piston 188, ametering chamber member 190, and a washer 192. Stem 152 further includesan elongate groove 194 at proximal end 154. A lumen 196 extends throughstem 152 at distal end 156 and terminates in a side port 198.

Valve 150 is shown in a closed configuration in FIG. 15. In the closedconfiguration, a first spring 200 biases a lip 191 of valve stem 152against washer 192, thereby placing the interior of container 144 influid communication with the interior of metering chamber member 190 viagroove 194. When in the closed configuration, the fluid within container144 fills metering chamber member 190 and overflows into the spacebetween insert 180 and metering chamber member 190 via holes 202. Thepressurized liquid in turn translates piston 188 and compresses a secondspring 204. Valve 150 is normally in the closed configuration so that aslong as fluid remains within container 144, liquid will compress secondspring 204 to fill valve 150 with liquid.

Dispensing of a unit volume amount of liquid from valve 150 isillustrated in FIG. 16. In FIG. 16, valve 152 is translated intocontainer 144 until elongate groove 194 no longer provides a fluid pathfrom container 144 into metering chamber member 190. At the same time,lumen 196 is placed in fluid communication with the interior of meteringchamber member 190 via side port 198. At this point, second spring 204expands (since the pressure in container 144 will not be available tokeep it compressed) to axially translate both piston 188 and O-ring 186within the space between insert 180 and metering chamber member 190.This in turn forces a unit volume of liquid from valve 150 where it willflow through lumen 196. After leaving lumen 196, the unit volume ofliquid will flow to thin shell member 162 via passage 160 as previouslydescribed in connection in FIG. 13.

After the unit volume of liquid has been dispensed from valve 150, firstspring 200 will again translate stem 152 against washer 192 as shown inFIG. 15 so that valve 150 may refill as previously described. In thismanner, each time stem 150 is translated into container 144, a unitvolume of liquid will be dispensed. Moreover, since substantially all ofthe liquid delivered to the thin shell member 162 will be nebulized,apparatus 128 may be employed to precisely deliver a unit dosage of amedicament to a patient.

Referring now to FIG. 17, another exemplary embodiment of an apparatus206 for nebulizing a liquid for prolonged treatments will be described.Apparatus 206 comprises a housing 208 which defines a chamber 210. Amouthpiece 212 is attached to housing 208 via a tube 214. Apparatus 206further comprises a base 216 which defines a liquid reservoir 218. Base216 includes a pin 220 which is placed within an L-shaped slot 222 onhousing 208. In this manner, base 216 may be removably attached tohousing 208 by inserting pin 220 into slot 222 and rotating base 216clockwise relative to housing 208. Base 216 further includes acylindrical opening 224 into which a wicking member 226 is received. Asdescribed in greater detail hereinafter, wicking member 226 draws fluidby capillary action from liquid reservoir 218 and to a thin shell member228 of a vibratable member 230. To assist in drawing liquid at anyorientation from liquid reservoir 218 into wicking member 226, liquidreservoir 218 may optionally include a plurality of capillary channels232. Liquid reservoir 218 is provided with a generally concave geometryso that liquid held therein will tend to flow toward cylindrical opening224 even when base 216 is significantly tilted. Capillary channels 232further assist in drawing any liquid to cylindrical opening 224 bycapillary action. In this manner, reservoir 218 is designed so thatsubstantially all of the liquid placed therein will be distributed tocylindrical opening 224 where it may be drawn by wicking member 226 upto thin shell member 228. In this way, no significant amount of liquidwill remain within reservoir 218, but will substantially all benebulized.

Vibratable member 230 is connected to housing 208 via an adapter 234,which also functions as a connector for an external power supply. Amounting plate 236 is placed between adapter 234 and vibratable member230. Vibratable member 230 and thin shell member 228 may be constructedessentially identical to embodiments previously described herein andwill operate in a similar manner. A lid 238 (see FIG. 20) is provided toenclose chamber 210.

Referring to FIG. 18, construction of wicking member 226 will bedescribed in greater detail. Wicking member 226 comprises an elongatebody 240 having a cylindrical base portion 242 and a cylindrical tip244. Base portion 242 may optionally include a capillary channel 246 toassist in drawing the liquid up the base portion 242. Additionalcapillary channels 248 are included in body 240 and extend up to tip 244to assist in drawing up liquid to tip 244. Tip 244 further includes aconcave well 250 which holds liquid drawn through capillary channels 248so that the liquid may be nebulized by the thin shell member 228.

Although the size of capillary channels 248 may vary depending upon thetype of liquid to be nebulized, capillary channels 248 will preferablyhave a gap in the range from about 50 μm to about 250 μm, and morepreferably from about 100 μm to about 200 μm.

Preferably, tip 244 will be in contact with thin shell member 228 duringvibration to ensure that liquid at tip 244 will be delivered to thinshell member 228. To ensure that wicking member 226 will not interferewith the vibration of thin shell member 228, wicking member 226 includesa plurality of cutouts 252 which provide body 240 with axialflexibility. The cutouts 252 therefore allow for manufacturingtolerances to be eased when constructing the wicking member. Body 240will preferably be constructed of an ABS plastic (which has good wettingcapabilities) so that, with the assistance of cutouts 252, body 240 willaxially flex as thin shell member 228 is vibrated. Wicking member 226may optionally be spring-loaded to prevent vibrational interference withvibratable member 230.

Referring now to FIG. 19, operation of apparatus 206 will be described.Initially, reservoir 218 is filled with an amount of liquid, such as aunit dosage of a liquid medicament. To assist in filling reservoir 218,base 216 may be separated from housing 208 as illustrated in FIG. 21.When filled, liquid within reservoir 218 will tend to settle (or bedrawn into) opening 224. As best shown in FIG. 20, cylindrical opening224 will be slightly spaced apart from cylindrical base portion 242 toprovide an annular capillary gap 254 therebetween. Gap 254 willpreferably be in the range from about 50 μm to about 250 μm, and morepreferably from about 100 μm to about 200 μm. In this manner, liquidwithin opening 224 will be drawn vertically up wicking member 226through capillary gap 254. Housing 208 further includes a cylindricalportion 256 which surrounds body 240 as shown. Cylindrical portion 256provides an annular gap 258 which is similar in size to capillary gap254. In this manner, liquid rising through capillary gap 254 willcontinue its travel up elongate body 240 via capillary cap 258. As therising liquid reaches capillary channels 248, the liquid continues itstravel toward tip 244 through capillary channels 248.

Vibratable member 230 includes a piezoelectric element 260 whichvibrates thin shell member 228 as previously described to eject liquidinto chamber 210. Hence, by employing wicking member 226, substantiallyall of the liquid supplied to reservoir 218 will be drawn to tip 244where it may be nebulized by thin shell member 228. In this manner, itcan be assured that all the liquid will be nebulized.

Referring back to FIG. 19, as thin shell member 228 nebulizes theliquid, a patient may inhale from mouthpiece 212 to drawn the nebulizedliquid from chamber 210. Chamber 210 includes at least one air hole 211so that air may be drawn through the mouthpiece 212 during patientinhalation.

As best shown in FIG. 21, upon completion of nebulization, base 216 maybe removed from housing 208. In this manner, apparatus 206 may easily becleaned. For example, once base 216 has been separated from housing 208,both pieces may be placed in a conventional dishwasher for cleaning andsterilization.

Referring now to FIG. 22, the manner of supplying power to apparatus 206will be described. Adapter 234 is configured to receive a connector 262of a DC adapter system 264. Adapter system 264 includes a male plug 266which may by inserted into, for example, a twelve volt DC power sourceof an automobile. A switch 268 is provided to regulate delivery of powerto apparatus 206. Switch 268 further includes a printed circuit board(not shown) which is similar to that board of FIG. 13 and which drivespiezoelectric element 260 as previously described.

Alternatively, a variety of other power sources may be employed tooperate apparatus 206. For example, as illustrated in FIG. 23, aconventional AC plug 270 may be provided to supply alternating currentto apparatus 206. The alternating current will preferably be convertedto DC power in order to drive piezoelectric element 206. Alternatively,internal batteries may be supplied to operate apparatus 206 similar tothe embodiment of FIG. 11 as previously described.

Although the foregoing invention has been described in detail forpurposes of clarity of understanding, it will be appreciated thatcertain changes and modifications may be practiced within the scope ofthe appended claims.

1-47. (canceled)
 48. A method for aerosolizing a liquid, the methodcomprising: providing an aerosolization device comprising an aerosolgenerator, an inhalation sensor, and control circuitry, wherein theaerosol generator comprises a plate having a plurality of apertures anda vibratable element that is mechanically linked to the plate, whereinthe vibratable element is configured to vibrate the plate, and whereinthe plate is non-planar in geometry; sensing a user inhalation with thesensor and transmitting an electrical signal to the control circuitry;sending a signal from the control circuitry to vibrate the vibratableelement when the inhalation reaches a threshold amount.
 49. A method asin claim 48, further comprising stopping vibration of the vibratableelement when the inhalation falls below the threshold amount.
 50. Amethod as in claim 48, wherein the inhalation is sensed by sensing airmoving through at least a portion of the aerosolization device.
 51. Amethod as in claim 48, wherein the vibratable element comprises apiezoelectric transducer, and further comprising sending an electricalsignal from the control circuitry to the piezoelectric transducer tovibrate the plate.
 52. An aerosolization device comprising: a housing;an aerosol generator operably coupled to the housing, wherein theaerosol generator comprises a plate having a plurality of apertures anda vibratable element that is mechanically linked to the plate, whereinthe aerosol generator is adapted to aerosolize a liquid for delivery toa user, and wherein the plate is non-planar in geometry; an inhalationsensor that is configured to sense when the user inhales and to producean electrical signal that is based on the sensed inhalation; controlcircuitry that is configured to actuate the aerosol generator when theelectrical signal indicates that the inhalation has reached a thresholdamount.
 53. A device as in claim 52, wherein the control circuitry isfurther control circuitry that is configured to actuate the aerosolgenerator when configured to stop actuation of the aerosol generatorwhen the electrical signal indicates that the inhalation has fallenbelow the threshold amount.
 54. A device as in claim 52, wherein theinhalation sensor is configured to sense air moving through at least aportion of the aerosolization device.
 55. A device as in claim 52,wherein the vibratable element comprises a piezoelectric transducer.